The long-term goal of our research project is to define mechanisms involved in regulating the formation, maintenance, and maturation of pre- and postsynaptic elements of the neuromuscular junction (NMJ). The NMJ is the chemical synaptic connection between motor neuron and skeletal muscle; it is essential for routine activities such as breathing, swallowing, and movement. We selected the NMJ as a model because it can provide information pertinent to both peripheral and central synapses, while its relatively simple structure and easy accessibility make it more amenable to investigation than the central synapse. This project addresses a fundamental question in the interaction between the pre- and postsynaptic elements of the NMJ - how muscle talks to nerve to establish and maintain normal NMJ patterns. Using genetic models in mice, we found that the dihydropyridine receptor (DHPR) - which is known for its role in muscle contraction - plays a crucial regulatory role in the development of innervation pattern and differentiation of motor neurons and motor nerve terminals. This finding was unexpected, in part because much of the information known about the regulation of the pre-synaptic development point to a predominantly neurocentric paradigm. The discovery of an important muscle-derived regulator suggests that muscle plays a much more active role in regulating presynaptic elements than was previously believed. Our findings provide a new avenue of investigation for identifying feedback mechanisms from muscle to nerve. We hypothesize that DHPRs in skeletal muscle regulate the differentiation of pre-synaptic nerve terminals and the survival of motor neurons in a retrograde fashion through its influence on the expression of muscle-specific genes. We plan to use a multidisciplinary approach to test this hypothesis and to elucidate the molecular mechanisms responsible for this regulatory activity. By identifying these regulatory signals, we may be able to provide additional targets for the development of therapeutic strategies to cure, control, or prevent neurodevelopmental disorders and neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: This project aims at defining mechanisms responsible for regulating the formation and maintenance of the NMJ. This is important because abnormal formation or function of the NMJ is implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Therefore, identifying regulatory mechanisms responsible for structural and functional changes in the NMJ will enable us to improve current treatment strategies for neurodegenerative diseases such as ALS and SMA.